DAY-NIGHT VARIATIONS IN THE RENAL EXCRETION OF THE ANTIARRHYTHMIC AGENT TIRACIZINE AND ITS METABOLITES

Daytime and nighttime urinary recovery as well as morning and evening trough serum levels of the antiarrhythmic agent tiracizine and three o f its metabolites (M1, M2, and M3) were assessed during a 7-day multip le-dose study period (50 mg tiracizine twice daily) in eight healthy v olunteers. A significantly lower mean steady-state urinary recovery wa s observed during the daytime as compared with during the nighttime (A e(tot tau d) = 42.0 +/- 15.7% vs. Ae(tot tau n) = 51.2 +/- 19.6%). Thi s difference is mainly due to a substantial increase of M1 and a small er increase of M2 urinary recovery by night. Results of additional in vitro investigations showed the ratio of the nonionic/ionic forms of M 1 and M2 to be highly dependent on pH in the range of pH 5-pH 7. There fore, the observed day-night variations might be attributed to alterat ions of ionization: i.e., nonionic tubular reabsorption of the metabol ites due to circadian differences in urinary pH. Trough serum levels o f Mi and M2 tended to be higher at 7 P.M. as compared with 7 A,M. Due to the narrow therapeutic index of class I antiarrhythmics, the presen t results indicate the need for further investigations concerning the effect of urinary pH on the pharmacokinetics of tiracizine and its met abolites.